HNSCC is the sixth most common cancer worldwide with an approximate 50% five-year survival rate. Two groups that independently studied the genetic origins of HNSCC reported inactivating mutations in NOTCH. This was the first strong evidence of NOTCH1 mutations in solid tumors and analysis of the mutations suggested that NOTCH1 might act as a tumor suppressor gene in HNSCC. Notwithstanding this important finding, and contrary to original expectations, these detailed analyses of HNSCC did not uncover a great number of recurrent somatic mutations in novel genes. The number of known mutations and specific mutational hotspots in HNSCC tumors only partially explain their biological complexity and limit the development of novel diagnostic markers and therapeutic agents. TP53 was again identified as the most commonly mutated gene in HNSCC, and while mutant TP53 has been associated with poor survival the most important biologic consequences of this alteration have been elusive. Moreover, it was also known that overall and disease-specific survival is higher in patients with HPV-associated HNSCC tumors, and that this distinct molecular and pathologic subtype displays an average of 4 somatic mutations per tumor, while HPV negative HNSCC tumors harbor about 20.
Aberrant methylation changes of CpGs in the proximity of predicted transcription start sites (TSS) are the main cause of alterations in gene function and pathway deregulation in human cancer. We hypothesized that epigenetic events, specifically inactivation of tumor suppressor genes through promoter methylation, are more frequent events than somatic mutations in cancer, and may be driving tumorigenic initiation and progression. Promoter methylation of CDK2NA, HOXA9, NID2, EDNRB, KIF1A, and DCC have previously been identified and characterized in HNSCC. We thus surmised that these epigenetic alterations predominantly occur in genes or pathways with well-known somatic mutations and/or deletions in most HNSCC tumors, including TP53, CDK2NA, and more recently NOTCH1 (1, 2) and FAT9, as well as in recently described genes with low frequency mutations. HNSCCs also exhibit many chromosomal abnormalities, including amplifications of the 11q13 region containing the cyclin D1 gene and the 7p11 region encoding EGFR, which lead to proto oncogene activation. Uncovering the concurrent genomic and epigenomic alterations that modulate gene function and differentially impact cell-signaling pathways can lead to improvements in personalized diagnosis, treatment, and clinical management of HNSCC patients.